Phosphorylation process plays an important role in the structural organization of neuronal cytoskeleton. Synthesis, transport and assembly of neurofilament (NF) proteins are regulated by specific kinases that extensively phosphorylate different motifs. The phosphorylation of NF proteins is developmentally and spatially regulated. Most of this phosphorylation takes place in the Lys-Ser-Pro (KSP) repeats in the carboxyl-terminal tail domain of NF-M and NF-H. This phosphorylation is believed to stabilize the NF network in the axon, and to affect the axonal transport and conduction velocity in the neurons. Some KSP sites of this tail domain in NF-H have been suggested to be phosphorylated by cyclin dependent kinase-5 (Cdk5). Cdk5 also phosphorylates tau protein and this phosphorylation occurs exclusively at the same sites found in the tau protein from Alzheimer's disease brain. Abnormal NF phosphorylation has also been associated with neurodegenerative diseases. In order to delineate precise roles of specific kinases in neurodegenerative process in vivo, we have initiated generation of the gene knockout mouse models for specific kinases and their activator subunits. Cdk5 null mouse exhibited unique brain lesions including a lack cortical laminar structure and cerebellar foliation. Additionally, the large neurons in the brain stem and in the spinal cord showed chromatolytic changes with the accumulation of NF immunoreactivity. Subsequent analysis of Cdk5 null phenotype revealed abnormal migration of cortical neurons. Most importantly, the abnormal migration of the neurons in these mice was not found to be associated with abnormal reelin expression indicating an inedpendent pathway through which Cdk5 exerts its effects on the neuronal migration and corticogenesis.